Schizophrenia Researchers Report Progress With Molecule Identified by Digital Gene's TOGA.

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LA JOLLA, Calif.--(BW HealthWire)--March 29, 2001

Gene Regulated in Clozapine Drug Mechanism May Help Explain Drug's

Benefit, Genesis of Pathology

Investigators at The Scripps Research Institute and Australia's Mental Health Research Institute of Victoria report an apparent role of Apolipoprotein D (ApoD) in the ameliorative effects conferred on schizophrenics by the neuroleptic drug, clozapine, and explore the possibility that systemic deficits in fatty acids metabolism may help explain elements of schizophrenia's pathology.

Writing in the current issue of the Proceedings of the National Academy of Sciences of the United States of America (PNAS) Vol. 98, No. 7, pp. 4066-4071 (2001), Elizabeth Thomas, Ph.D. and J. Gregor Sutcliffe, Ph.D., both of The Scripps Research Institute in La Jolla, and Brian Dean, Ph.D., and Geoffrey Pavey, Ph.D., of the Mental Health Research Institute of Victoria (Australia), report measurement of concentrations of ApoD in serum and various brain regions of human control, schizophrenic and bipolar subjects. They found a significant decrease in ApoD in serum, but significant focally increased concentrations of the atypical apolipoprotein in the dorsolateral prefrontal cortex and caudate regions of the brains of schizophrenic and bipolar subjects, regions previously associated with the pathophysiology of neuropsychiatric disorders such as schizophrenia.

Taken with previous observations reported by these researchers, the results suggest that region-specific levels of ApoD may be an important marker of neuropathology associated with neuropsychiatric disorders. Further, to the extent that the enhancement of ApoD levels may reflect the brain's attempt at compensation for a systemic deficit of the protein, clozapine's apparent stimulation of ApoD production may help explain the ameliorative effects conferred by clozapine on patients with schizophrenia.

The investigators were led to their focus on ApoD by studies applying Digital Gene Technologies' TOGA(TM) technology to assess gene expression changes in mouse brain samples over a two week time course following administration of the neuroleptic drug clozapine. Using TOGA(TM), the investigators were able for the first time to observe the full complement of genes regulated in the brain over an extended time course, and to focus on those that were significantly changed at the time points associated with known benefits of the drug in human patients. The study identified 14 such molecules (out of more than 11,000 expressed in these regions over the time course). The researchers have identified human homologues for several of the genes, including ApoD, and these have become the focus of the investigators' follow-up research into specific gene function. A report of the initial TOGA(TM)-based results was published in the Feb. 2001 issue of The Journal of Neurochemistry Vol. 76 (3): pp. 789-796, by Thomas, Patria E. Danielson, P. Austin Nelson, Thomas Pribyl, Brian Hilbush, Karl W. Hasel and Sutcliffe.

Reprints of the Proceedings article can be obtained from PNAS at: http://www.pnas.org/cgi/content/full/98/7/4066. Reprints of the Journal of Neurochemistry article can be obtained from the Journal at: http://www.jneurochem.org/cgi/content/full/76/3/789. Reprints of both articles are also available by email request to [e-mail].

The investigators' TOGA(TM)-based research into the molecular basis of neuropsychiatric pathologies such as schizophrenia and bipolar disorder is part of Digital Gene Technologies' unique academic collaboration program. The program includes 19 separate projects with researchers at many of the nation's leading research institutions and provides the opportunity to perform TOGA(TM)-based research, free-of-charge. Current projects involve a wide range of therapeutic fields including various cancers, diabetes, infectious diseases and neurodegenerative and neuropsychiatric disorders. The academic collaboration program is under the direction of the DGT scientific advisory board, and is designed to advance basic research and encourage publication, while reserving to DGT the commercial opportunities developed from TOGA(TM).

TOGA(TM) (an acronym for TOtal Gene expression Analysis) refers to DGT's proprietary method of identifying and determining the concentration of nearly all of the genes active in a sample cell or tissue. The method, developed at The Scripps Research Institute in the laboratory of Dr. J. Gregor Sutcliffe, a company founder and chairman of the DGT scientific advisory board, provides an inventory of gene activity in a sample and constitutes a major new approach to defining the function of the vast array of genes comprising any genome.

Digital Gene Technologies Inc. combines its patented TOGA(TM) genomics technology with advanced bioinformatics to identify and determine the expression patterns of the genes contained in any cell or tissue. The company has two complementary business objectives: (1) to develop gene expression-based research protocols with strategic partners and leading academic researchers; and, (2) to deploy its automated assay technology and proprietary databases in support of gene discovery and development of novel medical, agricultural and industrial products. A detailed description of DGT's TOGA(TM) method can be found in "TOGA(TM): An automated parsing technology for analyzing expression of nearly all genes," J. Gregor Sutcliffe, et al, Proceedings of the National Academy of Sciences of the United States of America, volume 97, issue 5, pp. 1976-81 (2000). For additional background, visit the DGT Web site at www.dgt.com.